Prognostic Genomic Biomarkers for Acute Myeloid Leukemia (AML) Based on French-American-British (FAB) Subtypes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5259-5259 ◽  
Author(s):  
Zheng Ping ◽  
Eleanor R McIntosh ◽  
Guo Tao ◽  
Dejun Shen ◽  
Vishnu Reddy
Keyword(s):  
Overall Survival ◽  
Gene Mutation ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Sequencing Data ◽  
Genomic Biomarkers ◽  
Tp53 Gene Mutation ◽  
Acute Myeloid

Abstract Background: The FAB classification system divides AML into eight subtypes, M0-M7, based on the blast cell morphology and its degree of myeloid maturation. It's an older system to classify AML, but is still used in some treatment protocols. Some prognostic factors related to patient and tumor characteristics have been previously described for AML, including age, Karnofsky score, and karyotype etc. However, the prognostic genomic biomarkers for detailed FAB subtypes of AML are not well defined. Design: Whole genome sequencing data were analyzed in 197 cases of AML. Twenty-four mutation genes and 38 copy number altered genes were selected based on change rate >=2% as a cutoff. Kaplan Meier Survival analysis for these genes was performed in five FAB subtypes (M0-M5). M6 and M7 are excluded from this study because of small sample size (M6, n=3; M7, n=3). All sequencing data and corresponding pathology information were from The Cancer Genome Atlas (Acute Myeloid Leukemia, TCGA provisional) and were analyzed via cBioPortal bioinformatics tool. Result: Total of seven mutation genes and two copy number altered genes show prognostic values. TP53 gene mutation is associated with worse overall survival in M0 (n=18). DNMT3A gene mutation is associated with worse overall survival in M1 (n=44). Gene mutations of NPM1, FLT3, IDH1 and gene amplification of KMT2A are associated with worse overall survival in M2 (n=44). BRINP3 gene mutation is associated with worse overall survival in M3 (n=21). TP53 gene mutation and gene amplification of KMT2A and ERG are associated with worse overall survival in M4 (n=39). KRAS mutation is associated with worse overall survival in M5 (n=22). (Log-rank test, p<0.05 for all tests) Conclusion: These data suggest that different FAB subtypes of AML could have unique prognostic genomic biomarkers. Compared with whole exome sequencing, targeted gene sequencing for these biomarkers may save time and money for patients. Further studies are necessary to understand the biological effects of these gene mutations/amplifications and confirm the above associations. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1981-1981
Author(s):  
Yang Xu ◽  
Zhen Yang ◽  
Hong Tian ◽  
Huiying Qiu ◽  
Aining Sun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 1981 Background: Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods: Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results: In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions: Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures: No relevant conflicts of interest to declare.

Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine

2014 ◽  
Vol 38 (7) ◽  
pp. 751-755 ◽  
Author(s):  
Cecile Bally ◽  
Lionel Adès ◽  
Aline Renneville ◽  
Marie Sebert ◽  
Virginie Eclache ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Tp53 Gene Mutations ◽  
Acute Myeloid

Marker Chromosomes Can Arise from Chromothripsis and Predict Adverse Prognosis in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2869-2869
Author(s):  
Tilmann Bochtler ◽  
Martin Granzow ◽  
Friedrich Stölzel ◽  
Christina Kunz ◽  
Brigitte Mohr ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Array Cgh ◽  
Newly Diagnosed ◽  
Single Chromosome ◽  
Marker Chromosomes ◽  
Acute Myeloid

Abstract Introduction: Cytogenetic testing is routinely performed in newly diagnosed acute myeloid leukemia (AML) for risk stratification. Elaborate risk classifications based on karyotyping are provided by both the European Leukemia Net (ELN) and the Medical Research Council (MRC). Complex aberrant, monosomal and abnl(17p) karyotypes confer a poor prognosis. In cytogenetic studies, chromosome aberrations that cannot be identified due to gross rearrangement, thereby preventing the allocation to a specific chromosome, are designated as "Marker Chromosomes" (MC). The significance of MC as prognostic factor for AML has remained elusive so far. In this study we have assessed frequency, cytogenetic characteristics and prognostic impact of MC as well as their underlying biological origin. Given the gross structural chromosomal damage inherent to MC we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. Patients and Methods: Patients recruited intwo large consecutive, prospective, randomized, multicenter clinical trials for newly diagnosed non-M3 AML patients from the German Study Alliance Leukemia (SAL) were analyzed (AML96, NCT00180115; AML2003, NCT00180102). All karyotypes were retrospectively screened for MC. For the detection of chromothripsis array-CGH was used. For each sample 50 ng of DNA were hybridized to an Affymetrix® CytoScan HD Oligo/SNP-array and scanned with the Affymetrix GeneChip® Scanner 3000 7G. Chromothripsis was defined according to the criteria of Rausch et al., which require at least 10 switches in segmental copy number involving two or three distinct copy number states on a single chromosome. Results: MC were detectable in 165/1026 (16.1%) of aberrant non-CBF karyotype cases. Adverse-risk karyotypes displayed a higher frequency of MC (40.3% in complex aberrant, 26.5% in adverse-risk as defined by MRC criteria and 41.2% in abnl(17p) karyotypes, p<.001 each). MC were associated with a poorer prognosis compared to other non-CBF aberrant karyotypes as well as with lower remission rates (CR+CRi; 36.0% vs. 55.8% in AML96 ≤60 years, p=0.01; 14.3% vs. 44.1% in AML2003, p<0.001), inferior event-free survival (2.24 vs. 6.54 months, p<0.001; 3.45 vs. 8.03 months, p<0.001) and overall survival (5.72 vs. 11.87 months, p<0.001; 8.68 vs. 20.78, p=0.01). In multivariate analysis with co-variables age, prior MDS, therapy-related AML and adverse-risk cytogenetics according to MRC criteria, MC independently predicted poor prognosis in AML96 ≤60 years but not in AML2003 with its higher allogeneic transplantation rate. As detected by array-CGH, in about one third of MC karyotypes (18/49, 36.7%, including 3 cases with 8 or 9 copy number switches) MC had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of complex aberrant karyotypes without MC (1/34) (p<0.001). Chromothripsis in MC karyotypes typically involved one single chromosome (n=11), with two or three chromosomes affected in 5 and 2 patients, respectively. There was no predilection for a particular chromosome. MC karyotypes positive for chromothripsis were characterized by a particularly high degree of karyotype complexity as compared to those that were negative for chromothripsis (complex aberrant 100% vs. 64.5% p<0.01; abnl(17p) 50.0% vs. 16.1%, p=0.01). In 12/18 (66.7%) cases, at least one of the chromothriptic chromosomes was reported as loss in the karyotype formula, suggesting that the grouping of a chromothriptic chromosome as a marker is paralleled by a putative loss of the affected chromosome. The chromothripsis positive MC karyotype subgroup had a particularly dismal prognosis with a combined CR+CRi rate of 2/16 vs. 10/31 (p=0.14). It also displayed inferior event-free and overall survival, though statistical significance was not reached for either endpoint, likely due to the already poor prognosis of the entire MC positive group. Conclusion: This is the first study showing that MC are a frequent finding predominantly in adverse-risk AML and associated with particularly poor prognosis. Our data provide evidence that a substantial portion of MC arise from chromothripsis. Disclosures Thiede: AgenDix: Employment, Other: Ownership.

scholarly journals Gene Mutation Profile and Risk Stratification in AML1-ETO-Positive Acute Myeloid Leukemia Based on Next-Generation Sequencing

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5249-5249
Author(s):  
Guopan Yu ◽  
Changxin Yin ◽  
Fuqun Wu ◽  
Ling Jiang ◽  
Zhongxin Zheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Gene Mutations ◽  
Kit Mutation ◽  
Mutation Profile ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Gene mutations play a critical role in leukemogenesis of AML1-ETO-positive acute myeloid leukemia (AE-AML). Nevertheless, gene mutation profile in this subtype leukemia remains unclear, and their clinical effect might be underestimated. In this study, we detested gene mutations at diagnosis and relapse with next-generation sequencing in 64 newly diagnosed AE-AML patients, and verified the results with Sanger sequencing at the same time. Our results showed that 68.8% patients presented recurrent mutations at diagnosis and 6/11 cases underwent genetic alterations at relapse. C-KIT mutation was the most common event at diagnosis, with an incidence of 42.2%, followed by ASXL1 (15.6%), MET (12.5%), MLH1 (9.4%) , TET2 (7.8%), and FBXW7, TP53 and DNMT3A (7.8%), etc. Also, C-KIT mutation was the most common molecular event associated with relapse (7/11, 63.6%). No significant difference in the clinical characteristic between the gene mutation and wild type (WT) groups was observed, except of higher incidence of additional cytogenetic abnormalities (ACAs) (P=0.025) in TP53 mutation patients. C-KIT (exon 8, 17) mutation but not exon 10 adversely affected on survival. Also ASXL1 and TP53 mutation were poor for the RFS (P<0.05), and ASXL1, MET, FBXW7 and TP53 mutation negatively impacted on the OS (P<0.05). Multivariate analysis showed C-KIT (exon 8, 17) and ASXL1 mutations were the independent adverse factors for survival. Further, co-mutation of these two genes showed even worse effect on survival. Taking together, additional gene mutations are critical in the development and progression of AE-AML. C-KIT and ASXL1 mutations are the two most common molecular events in this subtype leukemia. Single mutation of C-KIT (exon 8, 17) or ASXL1 poorly affects on survival, even worse in the co-mutation. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular study of Nucleophosmin 1(NPM1) gene in acute myeloid leukemia in Kurdish population

2021 ◽  
Vol 21 (2) ◽  
pp. 687-692
Author(s):  
Galawezh Obaid Othman ◽  
Nawsherwan Sadiq Mohammad ◽  
Chiman Hameed Saeed
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Treatment Decision ◽  
Molecular Study ◽  
Prognostic Indicators ◽  
Base Substitution ◽  
Molecular Abnormalities ◽  
Acute Myeloid

Background: In patients with Acute Myeloid Leukemia (AML) the most frequent acquired molecular abnormalities and important prognostic indicators is nucleophosmin-1 (NPM1) mutations. Our study aims was molecular study of Nucleop- hosmin -1 gene in Acute Myeloid Leukemia in Kurdish population. Patients &Methods: A total of 50 patients with AML, (36) of them attended Nanakaly Hospital and (14) attended Hiwa Hospital and 30 healthy subjects as control were selected randomly, all were matched of age and gender. Polymerase chain reaction (PCR) was used for detection of NPM1 gene mutation. Three samples of PCR product for NPM1 gene mutations were sequenced, and mutations were determined by comparison with the normal NPM1 sequence NCBI (GenBank acces- sion number NM_002520). Results: Out of 50 patients with AML, 5 (10%) of them were NPM1 gene mutation positive, and 45 (90%) were negative. The mutation were a base substitution (C to A), (G to C), (G to T), transversion mutation in addition of frame shift mutation and all mutated cases were heterozygous and retained a wild type allele. Conclusion: Identification of NPM1 mutations in AML are important for prognostication, treatment decision and optimi- zation of patient care. Keywords: Acute myeloid leukemia; Nucleophosmin-1 (NPM-1) gene mutation; PCR.

Prognostic Impact of Wilms Tumor 1 Single Nucleotide Polymorphism rs16754 In Older Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2701-2701
Author(s):  
Aline Renneville ◽  
Nicolas Boissel ◽  
Nathalie Helevaut ◽  
Olivier Nibourel ◽  
Christine Terré ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Gene Mutations ◽  
Minor Allele ◽  
Prognostic Impact ◽  
Single Nucleotide ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 2701 The Wilms tumor 1 (WT1) gene, located at chromosome band 11p13, encodes a transcriptional regulator involved in normal hematopoietic development. The role of WT1 in acute myeloid leukemia (AML) has been underlined by the finding of WT1 overexpression in most AML cases and WT1 gene mutations in approximately 10% of AML patients. Recently, the minor allele of the silent Arg301 single nucleotide polymorphism (SNP) (rs16754), which is a 903A>G substitution in WT1 exon 7, was suggested to predict a favorable prognosis in adult patients with cytogenetically normal (CN) acute myeloid leukemia (AML). In contrast, no prognostic impact of this SNP was found in another study performed in pediatric AML. Our aim was to evaluate the frequency, the main associated features and the prognostic significance of WT1 SNP rs16754 in elderly patients with AML. Diagnostic bone marrow or peripheral blood samples were analyzed from 266 patients (age 50 to 70 years) with previously untreated de novo AML included in the French ALFA-9801 trial. WT1 SNP rs16754 and gene mutations of NPM1, CEBPA, FLT3 (internal tandem duplication, ITD), WT1 (exon 7 and 9), IDH1 and IDH2 (exon 4) were screened on genomic DNA by direct sequencing and fragment-length analysis for the detection of small insertion/deletion. The minor allele of WT1 SNP rs16754 was found in 85 (32%) out of 266 cases. Patients heterozygous or homozygous for minor allele (WT1AG or WT1GG) and patients homozygous for the major allele (WT1AA) did not significantly differ in terms of age, gender, white blood cell (WBC) count, FAB subtypes, cytogenetic categories, and gene mutations when those mutations are considered separately. However, among CN-AML, the frequency of the favorable genotype defined by the presence of NPM1 mutation or CEBPA mutation without neither FLT3-ITD nor IDH1 mutation was significantly lower in patients with at least one minor allele than in patients with two major alleles (5% vs 23% of CN-AML, p=0.02). In univariate analysis, complete remission rate was found similar between patients with at least one minor allele and patients with two major alleles (76% vs 75%, p=0.88). Patients with at least one minor allele tended to have a shorter median delay to relapse (7 vs 12.2 months, p=0.06) and had a significantly shorter overall survival compared to patients with the two major alleles (5-year OS, 14% vs 26%, p=0.02). In the subset of CN-AML (n=113), the presence of at least one minor allele was also associated with a shorter median delay to relapse (6.9 vs 12.5 months, p=0.02) but only a trend regarding overall survival was observed (5-year OS, 17% vs 30%, p=0.1). In multivariate analysis considering age, WBC count, cytogenetics (favorable, intermediate and unfavorable categories) as covariates, WT1 SNP rs16754 status was found to be an independent prognostic factor for relapse risk (HR 1.56, 95% CI 1.06 to 2.30, p=0.03) and overall survival (HR 1.54, 95% CI 1.08 to 2.20, p=0.02). Thus, in our cohort of older AML patients, the minor allele of WT1 SNP rs16754 appears to confer a relatively poor prognosis, which is in contradiction to what has been reported so far. Overall, our data suggest that WT1 SNP rs16754 is an interesting marker that may contribute to refine prognosis in AML, at least in this age group of patients. Further investigations are needed to clarify the relationship between WT1 SNP rs16754 and treatment outcome in AML and elucidate the biological effects of this SNP. Disclosures: No relevant conflicts of interest to declare.

scholarly journals TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2114-2121 ◽  
Author(s):  
Frank G. Rücker ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Sabine Kayser ◽  
Veronica Teleanu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Complex Karyotype ◽  
Copy Number Alterations ◽  
Genomic Complexity ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as −5/5q−, −7/7q−, −16/16q−, −18/18q−, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

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